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Zawartość zarchiwizowana w dniu 2024-05-29

Role of the MCP-1/CCR2 system in the podocyte alterations of Diabetic Nephropathy: an in vivo and in vitro study

Final Activity Report Summary - MCP-1 and podocytes (Role of the MCP-1/CCR2 system in the podocyte alterations of Diabetic Nephropathy: an in vivo and in vitro study)

Diabetic nephropathy (DN), a microvascular complication of diabetes, is characterised by renal function decline and protein loss in the urine, named proteinuria. Proteinuria is not only a marker of renal damage, but also confers increased risk of cardiovascular mortality in patients with diabetes. Thus, proteinuria is an appropriate therapeutic goal and the clarification of the molecular mechanisms of proteinuria is of foremost importance to develop strategies for prevention and treatment.

The glomerular filtration barrier, which forms the final impediment to protein loss in the urine, is comprised of the glomerular endothelial cells, the glomerular basement membrane (GBM) and the podocytes. It is increasingly appreciated that defects in podocyte structure and function result in increased glomerular permeability. Podocytes are highly differentiated cells, composed of a cell body with major extensions and secondary extensions, i.e. foot processes. The foot processes of neighbouring podocytes interdigitate forming between them the filtration slits bridged by the slit diaphragm (SD). Several molecules including nephrin have been shown to be associated with the SD and to be critical for its integrity. Mutations in the nephrin gene are associated with the rare autosomal recessive disorder congenital nephrotic syndrome of the Finnish type, characterised by reduced or absent nephrin levels and massive proteinuria. Reduced nephrin expression has also been shown in animal models of DN and in type 1 and type 2 human DN.

Changes in podocyte morphology are also linked to proteinuria. The reorganizaton of foot process structure with broadening or flattening requires cytoskeleton remodelling, foot process movement over the GBM and SD reconstruction and may be considered as a migratory event that compensates for podocyte loss in proteinuric diseases. In addition, in animal models of glomerulonephritis (GN), podocytes display some characteristic features of migrating cells.

The factors which contribute to the evolution of proteinuria are not completely known, however, several inflammatory mechanisms have been proposed as being of relevance. Kidney macrophage accumulation is associated with the development of renal injury and a major factor influencing macrophage accumulation in the diabetic kidney is the chemokine monocyte chemoattractant protein 1 (MCP-1). MCP-1 specifically attracts blood monocytes and tissue macrophages via binding with its receptor CCR2. MCP-1 is overexpressed in the diabetic kidney and studies have shown that the blockade or deletion of MCP-1 had anti-proteinuric and renoprotective effects in both experimental DN and crescentic GN. The major mechanism by which MCP-1 contributes to renal damage is monocyte recruitment in the kidney. However, the CCR2 receptor is also found on other cells besides monocytes, suggesting that MCP-1 could act directly on renal cells to promote kidney damage.

In this study we investigated the way in which the MCP-1 and CCR2 system might be involved in the pathogenesis of proteinuric kidney disease. The results demonstrated that MCP-1 deficiency ameliorated both proteinuria and nephrin loss in experimental diabetes. In addition, cell studies showed that MCP-1 was able to act directly on podocytes to induce structural and functional changes relevant for chronic proteinuric kidney disease:

1. the MCP-1 receptor CCR2 was demonstrated on human podocytes
2. MCP-1 induced a reduction in nephrin expression via binding with its receptor
3. MCP-1 stimulated podocytes to acquire a migratory phenotype.

Furthermore, CCR2 was confirmed to be expressed by human podocytes in vivo and CCR2 expression was upregulated in patients with crescentic glomerulonephritis. Together, this data suggested that the MCP-1 and CCR2 system played a critical role in mediating molecular and structural alterations in podocytes relevant for the pathogenesis of DN, GN, and other proteinuric conditions.